We previously demonstrated statistical evidence for a major gene predisposing to cancer in kindreds of childhood and adolescent sarcoma patients. We had evidence for heterogeneity in risk by kindred, by generation, and by selected proband characteristics. The familial pattern of cancer evolved over time, with increasing evidence for a major gene after more than 20 years of observation. To date, some of the kindreds that provide strong evidence for a major gene have been found to have germline mutations in the tumor suppressor gene, p53. However, p53 can be ruled out as the cancer susceptibility locus in some clinically similar kindreds. We have characterized the risk in p53 mutation status, mutation type, sex, cancer site, smoking status, generation and age; surprisingly, there is heterogeneity in risk for all those factors except the mutation type, with truncating mutations conferring risks similar to those of missense mutations. Generation (or birth year, as they are confounded) is a major determinant of risk both in p53 mutation kindreds and non p53 cancer prone kindreds. We now propose to characterize the heterogeneity in risk using a strategy orf regressive models of segregation analysis, with additional critical years of observation. The strategy will be to identify residual cancer risk in the sarcoma kindreds, and to identify other major genes or modifying genes. The immediate goals are (1) in the p53 mutation kindreds, to identify the extent to which germline p53 mutations account for the observed familial cancer aggregation, to characterize further the phenotype, and to identify additional variation in risk, and (2) in the non p53 cancer prone kindreds, to identify the other major cancer susceptibility gene(s), to characterize the phenotype(s) and risk modifiers, and to define the genetic pathways that give rise to the phenotype(s). Findings from this project should provide information regarding the genetic etiology of childhood sarcomas and associated tumors, information for genetic counseling, and a resource from which to investigate the role of modifier loci in familial cancer aggregates.